Precision Treatment Pathways for MDD and Comorbid Insomnia

Introduction
Major depressive disorder (MDD) remains one of the most common psychiatric conditions worldwide, with lifetime prevalence rates nearing 15% and strong links to disability, morbidity, and suicide risk. Insomnia, marked by difficulty  falling or staying asleep, is reported in 85% of people with MDD and negatively impacts treatment outcomes and increases relapse risk.¹ Current data highlight that insomnia should not be viewed only as a symptom of depression but also as a potentially co-occurring condition that may need independent, mechanistically-targeted treatment approaches. This ECHO review examines emerging evidence, including phase 3 data on orexin-2 receptor antagonists such as seltorexant, and considers how such drugs might change how we manage MDD with insomnia in both community and academic settings.

The Clinical Intersection of MDD and Insomnia
People with MDD and insomnia are less likely to respond to antidepressants, have poorer quality of life, and possess higher risks of relapse and recurrence. Traditional management of MDD usually starts with SSRIs or SNRIs, which may not fully address sleep issues. Up to 60% of patients treated with SSRIs or SNRIs continue to experience residual insomnia despite improvements in core depressive symptoms.² Non-depressed people with insomnia have a twofold risk to develop depression, compared to people with no sleep difficulties.³ Cognitive behavioral therapy for insomnia (CBT-I) remains the primary non-drug treatment, endorsed by the American Academy of Sleep Medicine (AASM) and the American Psychological Association (APA), but barriers to access and adherence limit its use.⁴ Digital CBT-I programs have shown moderate to strong effectiveness, especially when guided by a therapist, though real-world adherence is variable.⁵

Current Pharmacologic Landscape and Unmet Needs
Several agents are used off-label to treat sleep disturbances in MDD, including treatment with lower (ie, nonantidepressant) doses of trazodone, quetiapine, and mirtazapine. Although trazodone is frequently prescribed for insomnia, AASM guidelines advise against using it as a first-line treatment due to limited effectiveness and high variability in next-day sedation, as well as limited evidence from trials and higher rates of adverse events.² Quetiapine and mirtazapine have sedative effects through histaminergic and serotonergic blockade, but both carry significant risks such as daytime drowsiness and weight gain. In the MIRAGE trial, mirtazapine 7.5 mg improved total sleep time and sleep maintenance in older adults but caused daytime sedation in 70% of participants and notable weight gain.⁶ These findings highlight the urgent need for a single treatment option that can effectively address both depressive and insomnia symptoms without increasing the risk of side effects.

Practice-Changing Data: The Seltorexant Phase 3 Program
Recent studies have highlighted seltorexant, a highly selective orexin-2 receptor (OX2R) antagonist that targets hyperarousal pathways involved in both depression and insomnia. The phase 3 MDD3001 trial enrolled nearly 500 adults with MDD and persistent insomnia despite SSRI/SNRI treatment. Over six weeks, adjunctive seltorexant 20 mg showed statistically significant improvements in both depression and sleep measures compared to placebo, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS) and the PROMIS-Sleep Disturbance scale.⁷ Notably, the effectiveness remained when the sleep item was removed from the MADRS, confirming that antidepressant effects were independent of sleep improvements.

Participants entering the one-year open-label extension phase maintained clinical benefits with sustained tolerability and no new safety concerns. Discontinuation-related adverse effects were minimal, indicating a favorable long-term profile. These findings represent a paradigm shift in managing MDD with comorbid insomnia by introducing a mechanistically-novel therapy that targets both conditions directly.

Comparative Efficacy: Seltorexant Versus Quetiapine XR
A subsequent 26-week, head-to-head phase 3 trial compared adjunctive seltorexant with quetiapine extended-release (XR) in patients experiencing residual insomnia after first-line antidepressant therapy.⁸ Both groups achieved similar reductions in depressive and insomnia symptoms, with over 50% clinical response in each. However, tolerability was better with seltorexant, which caused significantly fewer cases of somnolence, weight gain, and treatment discontinuation due to adverse events. Dropout rates were more than twice as high in the quetiapine XR group. These findings suggest that seltorexant is a well-tolerated, effective adjunctive option with a better risk–benefit profile compared to sedating antidepressant or antipsychotic augmentation strategies.

Integrating Evidence into Clinical Practice
The accumulated evidence supports a practice-changing approach: clinicians treating patients with MDD and persistent insomnia should evaluate sleep disturbance as a separate treatment goal. Using dual-action agents like seltorexant may enhance both mood and sleep results. Since insomnia can lead to relapse and hinder functional recovery, addressing this comorbidity can greatly improve long-term remission rates. Data from MDD3001 and the quetiapine comparator trial indicate that targeted OX2R antagonism provides strong antidepressant effects with fewer metabolic and sedative side effects, marking a significant advance for community practice.

Moreover, the safety and efficacy profiles of seltorexant fit with the increasing focus on personalized psychiatry. By targeting hyperarousal dysregulation, a common neurobiological factor in both depression and insomnia, clinicians can improve outcomes without the downsides of sedating adjuncts. The possibility of using it as a single agent or early in treatment makes OX2R antagonists potentially transformative for connecting mood and sleep regulation.

Novel Mechanistic Insights and Future Directions
Orexin signaling, mediated by hypothalamic neurons, controls wakefulness and stress responses. Dysregulated orexin levels contribute to hyperarousal and disrupted sleep patterns, both of which are linked to depression. By selectively blocking OX2R, seltorexant restores the sleep-wake cycle while influencing monoaminergic and hypothalamic-pituitary-adrenal axis activity, mechanisms that may explain its antidepressant effects.⁹

This mechanistic innovation sets OX2R antagonists apart from earlier hypnotics and sedating antidepressants, which act non-selectively on histamine, serotonin, or dopamine pathways and often impair daytime function. The dual-target potential of seltorexant offers a significant step forward from the current polypharmacy approach, where insomnia and depression are treated separately, increasing the risk of drug interactions and side effects.

Future research directions include evaluating the role of seltorexant in treatment-resistant depression, its potential as a monotherapy, and its possible synergy with digital CBT-I to maintain remission. Studies examining pharmacogenomic predictors of response could improve patient selection, advancing precision psychiatry.

Addressing Knowledge and Performance Gaps
Despite emerging data, awareness of new OX2R-targeting mechanisms remains limited in clinical practice. Many community clinicians continue to rely on sedative antidepressants or off-label antipsychotics because they are familiar and cost-effective. However, these approaches often fail to provide lasting benefits and pose metabolic and cognitive risks. Educational initiatives should highlight:

• Recognizing insomnia as a standalone, modifiable factor influencing depression outcomes
• Incorporating validated screening tools (eg, Insomnia Severity Index) into routine assessments for MDD
• Assessing patient eligibility for adjunctive treatments that target both mood and sleep
• Understanding the different risk profiles of traditional sedatives versus orexin antagonists

Such knowledge translation is crucial for shifting prescribing practices toward evidence-based, mechanism-specific interventions that improve both depression and insomnia outcomes.

Clinical Impact and Application
Assuming that sufficient efficacy and safety data emerge to justify FDA approval of seltorexant, clinical algorithms about management of MDD could be reshaped, especially for patients with residual insomnia after standard SSRI/SNRI therapy. Community clinicians should consider early assessment of sleep quality as part of depression monitoring. When insomnia persists, adjunctive seltorexant provides a well-tolerated alternative to quetiapine or mirtazapine, targeting two symptom domains without the sedative or metabolic side effects.

Methods to improve dissemination and implementation of practice guideline recommendations might also be needed to encourage greater use of CBT-I to address persistent insomnia in patients taking antidepressants. Data show that CBT-I can increase antidepressant response rates by 20-30% when used alongside medication.¹⁰ As access to digital CBT-I expands, integrating behavioral and pharmacologic treatments offers an evidence-based, scalable way to manage MDD with insomnia.

Conclusion
MDD with insomnia, whether as a feature of the depressive episode or a co-occurring condition, presents a complex clinical challenge because overlapping neurobiological mechanisms sustain both conditions. Traditional treatments often fail to effectively address this relationship, resulting in high relapse rates and reduced quality of life. Recent phase 3 evidence highlights seltorexant as a new, practice-changing adjunct therapy capable of providing the dual benefits of alleviating depressive symptoms and normalizing sleep, with better tolerability than traditional sedative antidepressants. By targeting the orexin-2 receptor pathway, seltorexant bridges the mechanistic gap between hyperarousal and mood dysregulation, offering a new approach to personalized depression treatment. To close the current healthcare gap, clinicians need to adopt a dual-focus treatment approach that combines mechanistic understanding, evidence-based pharmacotherapy, and accessible behavioral interventions to improve remission rates and overall patient functioning.

References 

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